The purpose of this project is to broadly support the NICHD clinical training program in reproduction and infertility. Clinical projects in the past year have investigated several issues of relevance to reproduction, including the assessment and reproductive outcome in women with a reduced number of oocytes (diminished ovarian reserve). Clinical studies completed during this period have suggested that the presence of fluid during treatment with gonadotropins was correlated with a reduced likelihood of pregnancy, possibly due to abnormal endometrial development. Additional studies are underway to further characterize markers of subtly impaired ovarian function, such as abnormal endometrial development. In a collaborative study with Dr. Nieman's group (PREB/NICHD) the unit has initiated basic studies of the disease of endometriosis designed to elucidate and characterize features of the abnormally implanted endometrial lesions in women. This collaborative project has begun, and in subsequent years we hope studies currently underway may foster new approaches for the treatment of endometriosis. Since estrogen is an essential hormone for the growth and development of reproductive tissues, the unit has continued basic research studies exploring the mechanism of action of estrogen in reproductive tissues. We have previously found that the Brx protooncogene greatly augmented estrogen action. In the past year in collaboration with Dr. Paul Driggers of the Department of Obstetrics and Gynecology of the Uniformed Services University, Brx has been found to increase activation not only estrogen receptor alpha, but also estrogen receptor beta. The ability of Brx to influence estrogen receptor beta activation is noteworthy given the localization of estrogen receptor beta in tissues such as the central nervous system, vascular system, lung and prostate. This fact lends support for the notion that the Brx protooncogene may have a physiologic role outside the reproductive system. Studies of Brx in cell lines revealed that activation of estrogen receptor beta by Brx required a p38 mitogen activated protein kinase pathway (MAPK), a signaling pathway distinct from the p44 MAPK pathway previously shown by other groups to influence estrogen receptor alpha activation. Thus, in the past year results have implicated a formerly unrecognized signaling pathway of estrogens involving Brx and p38 MAPK.